title: Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats.
abstract: BACKGROUND
  HX0969w is a novel water-soluble prodrug designed to release propofol and gamma-hydroxybutyrate (GHB) and has a sedative-hypnotic effect. This study was performed to compare the efficacy of HX0969w with fospropofol in mice and rats.
  
  
  METHODS
  We performed hydrolysis studies in the plasma from mice and rats. The half-maximal effective doses (ED50) and half-maximal lethal doses (LD50) of fospropofol and HX0969w were determined. A pharmacodynamics comparison of these two compounds was also performed. Time to loss of righting reflex, time to return of righting reflex, recovery time, and adverse effects were recorded.
  
  
  RESULTS
  The hydrolysis studies demonstrated that HX0969w released propofol as expected. HX0969w ED50 values in mice and rats were 133.03 and 53.79 mg kg(-1), respectively, and LD50 values were 607.11 and 283.79 mg kg(-1), respectively. The calculated therapeutic index (TI), safety index (SI), and certain safety factor (CSF) of HX0969w were 4.56, 3.33, and 2.92 for mice, and 5.28, 3.94, and 3.49 for rats, respectively. The pharmacodynamic comparison studies suggest that HX0969w has a longer onset time and shorter duration than fospropofol.
  
  
  CONCLUSIONS
  Similar to fospropofol, HX0969w is an effective, water-soluble prodrug that is capable of inducing a sedative-hypnotic effect in mice and rats. Unlike fospropofol, HX0969w releases GHB instead of formaldehyde. Further studies regarding the efficacy and safety of HX0969w are necessary.
authors.affiliation: Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: W S
authors.initials: WS
authors.lastname: Zhang
mesh_terms: D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D015742:Propofol / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012978:Sodium Oxybate / Q000378:metabolism; D012995:Solubility
chemical_list: C569054:2,6-diisopropylphenyl-4-hydroxybutanote disodium phosphate; D018686:Anesthetics, Intravenous; D009943:Organophosphorus Compounds; D011355:Prodrugs; D012978:Sodium Oxybate; C472965:fospropofol; D015742:Propofol
keywords: anaesthetics i.v., propofol; gamma-hydroxybutyrate; potency, anaesthetic, ED50; water-soluble prodrug